OP0208 MECHANICAL UNLOADING PREVENTED ARTHRITIS IN THE RAT ADJUVANT-INDUCED ARTHRITIS MODEL
Authors: E. Dalix, M. Maalouf, A. Vanden-Bossche, M. Paul, H. Marotte
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatic disease, characterized by synovitis associated with progressive bone loss and joint swelling. The adjuvant-induced arthritis (AIA) model mimics the pathophysiological features of RA, with a very high prevalence and reproducibility. YAP plays a key role in synovial hyperplasia. It is a transcription factor which can be activated in response to inflammation but also by a mechanical stimulus as tissue stiffening. We already showed a decrease arthritis severity by inhibiting YAP in the AIA model [1]. Then, different mechanical challenges could potentially impact arthritis development by regulating YAP. <h3>Objectives</h3> The objective of this study was to investigate the impact of mechanical loading and unloading on the development of arthritis in the AIA model. <h3>Methods</h3> Arthritis was induced in female Lewis rats by injection of the adjuvant <i>Mycobacterium butyricum</i>, defining day (D)0. The AIA model normally develops arthritis at D10, with a peak of inflammation at D17 [2]. Rats were randomized into three groups: an AIA+mechanical loading group (n=11) with free access to an activity wheel from D0 to D17, an AIA+mechanical unloading group (n=11) by tail suspension from D0 to D17, and an AIA-only group (n=11) as positive control. Daily clinical monitoring (arthritic index and ankle circumference) was used to follow the progression and severity of arthritis. At D17, the ankles of the rats were collected to perform RT-qPCR. <h3>Results</h3> Arthritis onset was observed at the same time (D10) in the AIA control and AIA+mechanical loading groups with the same kinetic of arthritis index and ankle circumferences. However, the majority of rats in the AIA+mechanical unloading group did not develop any signs of arthritis. At D17, gene expression of YAP and CYR61 (YAP target gene), IL1B, IL6, RANKL, ACP5 (encoding TRAPc), CTSK (encoding cathepsin K), MMP9, and MMP13 was decreased in the ankle of AIA+mechanical unloading rats compared to other groups. In the AIA+ mechanical loading group, rat stopped their physical activity at D10 which may explain the lack of clinical and molecular differences between the AIA and AIA+mechanical loading groups at D17. <h3>Conclusion</h3> Mechanical unloading of the hindpaws by the suspension system strongly prevented arthritis by a reduced expression of pro-inflammatory genes, bone resorption, and bone degradation genes. The decrease in inflammation may be partly explained by the decrease in YAP transcriptional activity. Mechanical stress is therefore a key factor in inflammation during AIA. The precise mechanisms linking these two mechanisms are still under investigation. <h3>References</h3> [1]Caire R, Audoux E, Courbon G, Michaud E, Petit C, Dalix E, et al. YAP/TAZ: Key Players for Rheumatoid Arthritis Severity by Driving Fibroblast Like Synoviocytes Phenotype and Fibro-Inflammatory Response. <i>Front Immunol</i> 2021;12:791907. [2]Courbon G, Cleret D, Linossier M-T, Vico L, Marotte H. Early Subchondral Bone Loss at Arthritis Onset Predicted Late Arthritis Severity in a Rat Arthritis Model: EARLY BONE LOSS AT ARTHRITIS. <i>J Cell Physiol</i> 2017;232:1318–1325. Available at: http://doi.wiley.com/10.1002/jcp.25601. Accessed October 20, 2020. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.